Apoptosis in Embryonic Development

Apoptosis, or programmed cell death, is a
mechanism in embryonic development that occurs naturally in
organisms. Apoptosis is a different process from cell necrosis,
which is uncontrolled cell death usually after infection or specific
trauma. As cells rapidly proliferate during development, some of them
undergo apoptosis, which is necessary for many stages in
development, including neural development, reduction in egg cells
(oocytes) at birth, as well as the shaping of fingers and vestigial
organs in humans and other animals. Sydney Brenner, H. Robert
Horvitz, and John E. Sulston received the Nobel Prize in Physiology
or Medicine in 2002 for their work on the genetic regulation of
organ development and programmed cell death. Research on cell
lineages before and after embryonic development may lead to new ways
to reduce or promote cell death, which can be important in
preventing diseases such as Alzheimer's or cancer.

Karl Vogt observed the phenomenon of apoptosis in
Neuchâtel, Switzerland, in 1842, but Vogt did not use the term
apoptosis. Vogt noticed in midwife toad (Alytes
obstetricans) embryos that cells in the notochord, a
cartilaginous skeletal structure, disappeared and were replaced by
cells of the vertebrae. Although Vogt documented that some cells
disappeared during development, he did not focus his research on
that phenomenon. Researchers did not give apoptosis very much
attention until 1885 when Walther Flemming, who worked at the
University of Kiel in Kiel, Germany, used more advanced staining
techniques on the cell nucleus to observe what he called
chromatolysis, the diminishing of nuclear material in dying cells.
Chromatolysis is part of the process of apoptosis, but Flemming's
research was overshadowed until biologist Alfred
Glücksmann, who worked at the Strangeways Research Laboratory in
Cambridge, England, published a review on cell death literature in
1951.

In his review, Glücksmann hypothesized that for an organism to
grow and develop, cell death must occur. At the time of Glücksmann's
review, many scientists interpreted dead cells as metabolic
byproducts of cells undergoing mitosis, or cellular replication.
Glücksmann presented evidence from past embryological research that
described planned cell death as an aspect of normal development.
Glücksmann's hypothesis remained largely unnoticed for more than
twenty years. However, John F. Kerr, Andrew H. Wyllie, and Alastair
R. Currie, pathologists working at the University of Aberdeen in
Aberdeen, Scotland, referenced Glücksmann's review as motivation to
develop their own research on apoptosis in 1972.

Kerr had first studied cell death in 1965 when he noticed
atrophy, or shrinkage, in rat liver cells under an electron
microscope. Kerr noticed that the shrinkage was distinct from
necrosis due to trauma, which normally causes the cell to rupture
and release its contents. A few years later, Kerr and his colleagues
noted common patterns involved in cell death related to their
research and recorded in previous experiments and reviews, including
Glücksmann's work. Kerr and his team framed their research focus as about
programmed cell death, a concept that Richard Lockshin and Carroll
Williams at St. John's University New York City, New York, had
used in 1964. Kerr and his colleagues coined the term apoptosis
to describe programmed cell death. They claimed that cell death from
apoptosis was not accidental, and that it followed the same pattern
in both developing and developed cells. With their 1972 article,
Kerr and his team brought the idea of apoptosis to greater
scientific attention.

Kerr, Wyllie, and Currie's research clarified the process of
apoptosis as a series of specific steps, later verified by other
researchers. First, cells undergoing apoptosis begin to shrink in
size and lose physical connections with neighboring cells. Second,
the chromatin, or the combination of DNA and protein within the cell
nucleus, condenses and enzymes begin to fragment the chromatin
within the cell. Third, the cell membrane bulges irregularly, or
blebs. Fourth, the nucleus collapses and breaks into fragments
containing pieces of chromatin, while the cell continues to bleb.
Fifth, the cell breaks into several smaller membrane bodies that
contain various cellular fragments, called apoptotic bodies. Lastly,
white blood cells, also called phagocytes, or neighboring cells
engulf the apoptotic bodies and break them down. The organism
suffers no major injury as a result.

After Kerr, Wyllie, and Currie published their research,
scientists accepted apoptosis as a mechanism in cellular development
and began to study its significance in development and disease. For
example, since the 1970s Sydney Brenner in Berkeley, California, Robert Horvitz in Cambridge,
Massachusetts, and John
Sulston in Cambridge, England, conducted much of their early
research on the nematode Caenorhabditis
elegans(C. elegans). Through diagrams of cell
lineages and careful documentation, Brenner, Horvitz, and Sulston
predicted when cell death would occur, and they identified some of
the genes involved in the regulation of cell death. In particular,
Horvitz noted that C. elegans neurological development
included a large amount of apoptosis, with 105 of the 131 programmed
cell deaths occurring in neural cells. Brenner, Horvitz, and Sulston
received the Nobel Prize in Physiology or Medicine in 2002 for their
work in genetic regulation of organ development and programmed cell
death.

Research conducted after Brenner, Horvitz, and Sulston published
their findings on C. elegans reinforced the
theory that programmed cell death through apoptosis is essential for
development in animals. In 1993, scientists working with Horvitz
found that a gene in mice was very similar to the gene that codes
for an enzyme that causes cell death during development in C.
elegans. The research showed that the apoptosis observed in
C. elegans also occurs in mammals.

In 1997, Michael Jacobson and researchers at the MRC Lab of
Molecular Biology in Cambridge, England, outlined the importance of
cell death in animals in the article "Programmed Cell Death in
Animal Development". Jacobson and colleagues claimed that the
primary functions of apoptosis are to sculpt the organism by
deleting unwanted structures, controlling the number of cells, and
eliminating nonfunctional, harmful, abnormal, or misplaced cells.
Absence of apoptosis can include malformations of digits, decreased
neurological function, malformations of the heart, or even cancer.
For example, soft tissue cells between the fingers and toes undergo
apoptosis in order to separate the digits from each other during
development. The proper formation of heart loops also relies on the
process of apoptosis.

In his article "The Apoptotic Oocyte," Gary Wessel from Brown
University in Providence, Rhode Island, discusses the role of
apoptosis in human females. Human female oocytes undergo apoptosis
during development and after birth. Scientists estimate that seven
to eight million oocytes are formed in the fetus, which are reduced
to about 100,000 oocytes at birth, and then only a few hundred at
the onset of menopause.

Apoptosis occurs not only during embryonic development, but also
after birth. In humans for example, brain cells undergo apoptosis
prior to and following birth to eliminate excess brain cells and
streamline nerve impulses. Apoptosis also occurs in some cells that
the body identifies as cancerous to prevent the spread of
the cancer and kill the cancerous cells. However, unregulated
apoptosis can cause disorders, such as Alzheimer's disease and amyotrophic lateral
sclerosis, which is a motor neuron disease.